X-53217264-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_004187.5(KDM5C):c.536G>A(p.Arg179His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,209,054 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 121 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R179C) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., 4 hem., cov: 22)

Exomes 𝑓: 0.00035 ( 0 hom. 117 hem. )

Consequence

KDM5C
NM_004187.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 2.20

Publications

11 publications found

Variant links:

Genes affected

KDM5C (HGNC:11114): (lysine demethylase 5C) This gene is a member of the SMCY homolog family and encodes a protein with one ARID domain, one JmjC domain, one JmjN domain and two PHD-type zinc fingers. The DNA-binding motifs suggest this protein is involved in the regulation of transcription and chromatin remodeling. Mutations in this gene have been associated with X-linked cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

KDM5C Gene-Disease associations (from GenCC):

syndromic X-linked intellectual disability Claes-Jensen type
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
X-linked syndromic intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

KDM5C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11263651).

BP6

Variant X-53217264-C-T is Benign according to our data. Variant chrX-53217264-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211252.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000351 (385/1097668) while in subpopulation NFE AF = 0.000437 (368/841841). AF 95% confidence interval is 0.0004. There are 0 homozygotes in GnomAdExome4. There are 117 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM5C	NM_004187.5 link	c.536G>A	p.Arg179His	missense_variant	Exon 5 of 26	ENST00000375401.8	NP_004178.2	P41229-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM5C	ENST00000375401.8 link	c.536G>A	p.Arg179His	missense_variant	Exon 5 of 26	1	NM_004187.5	ENSP00000364550.4		P41229-1

Frequencies

GnomAD3 genomes

AF:

0.000180

AC:

AN:

111386

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000981

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000320

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000204

AC:

AN:

181381

AF XY:

0.000151

show subpopulations

Gnomad AFR exome

AF:

0.0000765

Gnomad AMR exome

AF:

0.000219

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000360

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000351

AC:

385

AN:

1097668

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

117

AN XY:

363038

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26396

American (AMR)

AF:

0.000171

AC:

AN:

35179

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19373

East Asian (EAS)

AF:

0.00

AC:

AN:

30195

South Asian (SAS)

AF:

0.00

AC:

AN:

54022

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40487

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4108

European-Non Finnish (NFE)

AF:

0.000437

AC:

368

AN:

841841

Other (OTH)

AF:

0.000195

AC:

AN:

46067

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000180

AC:

AN:

111386

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

33558

show subpopulations

African (AFR)

AF:

0.0000981

AC:

AN:

30573

American (AMR)

AF:

0.00

AC:

AN:

10536

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3551

South Asian (SAS)

AF:

0.00

AC:

AN:

2629

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5993

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000320

AC:

AN:

53058

Other (OTH)

AF:

0.00

AC:

AN:

1492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000208

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.000231

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Dec 16, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 26, 2018

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28912153, 26580603) -

Jul 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 27, 2017

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

KDM5C-related disorder

Benign:1

Dec 07, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

.;T;.;.;.

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.63

T;T;T;T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.46

.;N;.;N;.

PhyloP100

2.2

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.67

N;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.23

T;T;T;T;T

Sift4G

Benign

0.17

T;T;T;T;T

Polyphen

0.0010

.;B;.;.;.

Vest4

0.22

MVP

0.77

MPC

1.7

ClinPred

0.024

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.59

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over